KR100509351B1 - A double capsule for the administration of active principles in multiple therapies - Google Patents

Abstract

Disclosed is a pharmaceutical dosage form particularly suited for the administration of the active ingredient in combination therapy. The pharmaceutical dosage form is a double capsule in which the inner capsule is located inside the outer capsule. Each inner and outer capsule contains one or more active ingredients. Double capsules according to the invention are preferably used for triple or quadruple treatment against microbial Helicobacter pyrroli. The advantage of the medicament dosage form is that it provides a simple dosage in administering two or more active ingredients, allows the active ingredients to be activated at appropriate time intervals and in appropriate amounts, and prevents interaction between the active ingredients. In a preferred embodiment of the invention, the medicament dosage form has an outer capsule containing bismuth subcitrate and metronidazole, and an inner capsule containing tetracycline and any omeprazole, which is a treatment for eradicating Helicobacter pyrroli. Used for

Description

A DOUBLE CAPSULE FOR THE ADMINISTRATION OF ACTIVE PRINCIPLES IN MULTIPLE THERAPIES}

The present invention relates to a pharmaceutical dosage form consisting of double capsules for the administration of the active ingredient for use in combination therapy. The double capsule consists of another capsule located inside the capsule.

Therapies for administering two or more active ingredients at once or at some interval are already known. The most common pharmaceutical dosage forms consist of tablets for various active ingredients with a coating that allows for the differentiated release of chemicals.

Of these therapies, the most commonly used are therapies associated with gastrointestinal diseases such as gastritis and gastroduodenal ulcers, caused by the presence of microbial Helicobacter pylori, and which can develop into tumor form. As is already known, Helicobacter pylori is the modern name of Campilobacter pylori.

US 5,196,205 (corresponding to patent application WO 89/03219) describes a method for treating such a bacterium, which administers a bismuth compound, a first antibiotic belonging to the penicillin and tetracycline classes, and a second antibiotic such as metronidazole. It consists of. The regimen consists of administering three tablets several times a day each containing one active ingredient. As a result, this treatment is very complex.

The treatment disclosed in US Pat. No. 5,196,205 was complemented by the addition of omeprazole, which irreversibly inhibits the fourth active ingredient, the enzyme H + / K + ATP, thereby reducing gastric gland secretion. Omeprazole should be administered at a different time than the active ingredient mentioned above, which may be determined by other factors that may affect the severity of the disease, the age and the effect of the patient.

Therefore, treatments requiring complex posi- tions, such as combination therapies, are likely to cause mistakes that undermine the outcome of treatment.

Other patents and patent applications are disclosed that describe single or multiple treatments for eradicating Helicobacter pyrroli, such as US 5,472,695, US 5,560,912, US 5,582,837, WO 92/11848 and WO 96/02237. None of the foregoing patents and patent applications overcomes the problem of interactions between the active ingredients in a simpler and more inventive manner than proposed in the present invention.

US 5,310,555 and US 5,501,857 describe the use of double capsules to deliver nutritional supplements to animals. JP 60-193917 describes soft capsules containing several small soft capsules. Or a standard hard capsule having a hard gelatin capsule therein with different dissolution properties. FR 2,524,311 describes double capsules and triple capsules. FR 1,454,013 describes double capsules in which the inner capsule has delayed release properties. GB 2,103,564 describes a capsule structure for oral administration of a prophylactic drug that allows a user to break an external capsule and swallow the external capsule completely, which consists of a fragile outer capsule and an edible inner capsule. And an air layer therebetween.

Among the combined therapies to eradicate Helicobacter pyrroli, the following active ingredient combinations have been tested in humans and are published:

1. Amoxicillin, Metronidazole and Furazolidone;

2. bismuth subsalicylate, lansoprazole and clarithromycin;

3. bismuth subsalicylate, roxytromycin, metronidazole and ranitidine;

4. clarithromycin, colloidal bismuth subcitrate and furazoline;

5. Colloidal Bismuth Subcitrate, Amoxicillin and Metronidazole;

6. Ebrotidine, Amoxicillin and Metronidazole;

7. Lansoprazole, Amoxicillin and Azithromycin;

8. lansoprazole, amoxicillin and clarithromycin;

9. Lansoprazole, Amoxicillin and Levamifeed;

10. lansoprazole, clarithromycin and furazoline;

11. Lansoprazole, Azithromycin and Metronidazole;

12. Lansoprazole, Myconazole and Amoxicillin;

13. Lansoprazole and norfloxacin;

14. metronidazole and dirithromycin;

15. Omeprazole, amoxicillin and azithromycin;

16. omeprazole, amoxicillin, clarithromycin and metronidazole;

17. Omeprazole, amoxicillin, metronidazole and bismuth;

18. Omeprazole, amoxicillin and levamifeed;

19. Omeprazole, amoxicillin and tinidazole;

20. Omeprazole and amoxicillin;

21. Omeprazole and azithromycin;

22. Omeprazole, bismuth and ciprofloxacin;

23. Omeprazole, bismuth and clarithromycin;

24. Omeprazole, clarithromycin and tinidazole;

25. Omeprazole and dirithromycin;

26. Omeprazole, lansoprazole and levamifeed;

27. Omeprazole, metronidazole and amoxicillin;

28. Omeprazole, metronidazole and azithromycin;

29. Omeprazole, metronidazole and clarithromycin;

30. Omeprazole and norfloxacin;

31. Omeprazole, sucralate, metronidazole and tetracycline;

32. Omeprazole, clarithromycin and tinidazole;

33. Pantoprazole, clarithromycin and amoxicillin;

34. pantoprazole and clarithromycin;

35. ranitidine bismuth citrate, clarithromycin and tetracycline;

36. ranitidine bismuth citrate and clarithromycin;

37. ranitidine bismuth citrate, metronidazole and clarithromycin;

38. ranitidine bismuth citrate and cefuroxime;

39. Rifaximin and erythromycin;

40. Omeprazole, bismuth, tetracycline and metronidazole;

41. Omeprazole, bismuth subcitrate, tetracycline and metronidazole;

42. Bismuth subcitrate, tetracycline and metronidazole.

Summary of the Invention

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It is an object of the present invention to provide a use as a treatment of microbial Helicobacter pyrroli in medicament dosage form wherein one capsule comprises two capsules located inside another capsule, each containing one or more active ingredients.

According to the present invention, the above object is a soluble salt of bismuth, a first antibiotic and a second agent for the preparation of a medicament dosage form comprising two capsules in which one capsule is located inside the other capsule for triple treatment of microbial Helicobacter pyrroli. Achieved by the use of antibiotics, the outer capsule contains a soluble salt of bismuth and a first antibiotic, and the inner capsule contains a second antibiotic. The object of the present invention is also intended for the quadruple treatment of microbial Helicobacter pyrroli. For the use of bismuth soluble salts, first antibiotics, second antibiotics and K ⁺ / Na ⁺ ATPase inhibitors or anti-H ₂ for the preparation of a pharmaceutical dosage form comprising two capsules in which the capsule is located inside another capsule. is achieved by, the external capsule contains a soluble salt of bismuth and the first antibiotic, the capsule is a second antibiotic, and a K ⁺ / Na ⁺ ATPase inhibitor or Tea contains a -H _2. An object of the present invention it is also a bi-soluble salts for the preparation of a first pharmaceutical dosage form and a second pharmaceutical dosage form for a quadruple therapy for Helicobacter microbes pyrrolidone, a first antibiotic, a second antibiotic And two capsules, one capsule of which is located inside of another, wherein the outer capsule is a soluble salt of bismuth, and is achieved by the use of a K ⁺ / Na ⁺ ATPase inhibitor or an anti-H ₂ . It contains a first antibiotic, the inner capsule contains a second antibiotic, and the second medicament dosage form contains a K ⁺ / Na ⁺ ATPase inhibitor or anti-H ₂ .

An advantage of the pharmaceutical dosage form of the present invention is that it can be used in combination therapy to allow safe and simple dosages.

One of the important advantages of the pharmaceutical dosage form of the present invention is that the problems associated with the interaction between the active ingredients can be overcome by physical boundaries.

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The features and advantages of the invention will be better understood by the following non-limiting description.

Double capsule

The present invention provides a new medicament dosage form for administration of an active ingredient for use in combination therapy, in which one of the two capsules is located inside the other capsule, each capsule containing one or more active ingredients. The medicament dosage form is called a double capsule, and the two capsules are called an internal capsule and an external capsule, respectively.

Both inner and outer capsules are preferably made by hard gelatin. If desired, the inner capsule can be made by gelatin treated to be gastroresistant and low release.

Commercial capsules are distinguished by numbers or letters according to size (length, diameter and thickness), as described in Table 1 (CAPSUGEL MULTISTATE FILE, 2 ° Ed.)

All combinations of Table 1 in accordance with this principle are possible, provided that the double capsule according to the invention has fewer inner capsules than the outer capsule and is not a combination of an outer capsule of format 0+ and an inner capsule of format A or 0. Such combinations are selected depending on the increase in usefulness for the patient and the amount of material introduced in both capsules. In fact, the volume between the two capsules and the volume of the inner capsule should be suitable to insert the single dose required for treatment. Preferably, the inner capsule is in 2 or 3 format, and the outer capsule is in 0+ or 1 format, respectively. In a preferred embodiment of the invention, the inner capsule of format 3 is inserted into the outer capsule of format 0+.

The pharmaceutical form is realized by an intermittent or continuous actuated capsule filling machine which is equipped with a dosator for filling an empty capsule with powder, tablets, pellets or filled capsules. Examples of such capsule fillers include Zanazi 40 from Bologna's IMG and MG Futura level 02 from Bologna's MG2. As an alternative, a new double capsule can be realized by means of a handheld type Zuma 150 or 300 and a type Parke-Davis / Capsugel.

In addition, it should be taken into account that the movement of the capsule caused by automatic or manual capsule filling and the simple operation of inserting the inner capsule should be able to form a powder layer separating the two capsules between the two capsules.

Triple therapy

The pharmaceutical dosage form consists of administration of three active ingredients consisting of soluble bismuth salts, a first antibiotic and a second antibiotic, for use in triple therapy for the eradication of hospital Helicobacter pylori (also known as Campylobacter pylori). Especially appropriate.

Bismuth salts include bismuth subcitrate, bismuth aluminate, bismuth carbonate, bismuth citrate, colloidal bismuth subnitrate, bismuth germanate, bismuth germanium oxide, bismuth nitrate, bismuth oxide, bismuth oxychloride, bismuth phosphate, bismuth It is preferably selected from the group consisting of salicylate, bismuth subcarbonate, bismuth subnitrate, bismuth subsalicylate, bismuth tribromophenate, bismuth trioxide, bismuth vanadate and bismuth vanadium tetraoxide. Bismuth salts can be used in the form of complex salts. For example, bismuth biscalitrate is a complex salt form of bismuth subcitrate.

The first antibiotic is preferably selected from the group consisting of nitroimidazoles. Nitroimidazoles are metronidazole, apronidazole, azomycin, benzonidazole, carnidazole, demethidazole, ethanidazole, flunidazole, misnidazole, nimorazol, ornidazole, panidazole, loni It is preferably selected from the group consisting of dozol and tinidazole.

The second antibiotic is preferably selected from the group consisting of macrolides and tetracycline compounds. Macrolides are preferably selected from the group consisting of azithromycin, clarithromycin, and erythromycin. The tetracycline-based compound is preferably selected from the group consisting of tetracycline, chlortetracycline, doxycycline, glycocycline, guamecycline, limethicline, methacycline and sancycline. As is known in the art, tetracycline corresponds to tetracycline hydrochloride.

In a preferred embodiment of the invention, the outer capsule contains bismuth subcitrate and metronidazole, and the inner capsule contains tetracycline.

When the outer capsule, preferably the outer capsule containing bismuth subcitrate in complex form and metronidazole, dissolves, the complexing bismuth causes a healing gel to form in the stomach. After a predetermined time has elapsed, according to the treatment instructions, the inner capsule is dissolved and tetracycline is released, which acts on the stomach.

The aforementioned triple treatment, which typically consists of administering two identical double capsules several times a day, need not be concerned about the order of administration and the manipulation of the double capsule. Capsules should be taken before meals and before evening snacks.

Quadruple therapy

Another realization method of the present invention consists of the administration of a fourth active ingredients, such as a K ⁺ / Na ⁺ ATPase inhibitor or anti--H ₂ (anti-H ₂₎ with the double capsule described above. In this case, the double capsule according to the present invention is used for quadruple treatment for diseases of the digestive system. K ⁺ / Na ⁺ ATPase inhibitor or anti-H ₂ is BY841; Cimetidine; Ebrotidine; Ethyntidine; Pamotidine; Flunarizine; ICI-162,846; Lansoprazole; Metiamide; Mifentidine; Niferotidine; Nizatidine; Omeprazole; Oxmetidine; Pantoprazole; Rabeprazole; Lamyxotidine; Ranitidine; Ritanserine; Roxatidine acetate hydrochloride; ZKF-93479; SKF-94482; Supotidine; Thiotidine; TY-11345; Wy-45,727; And zaltidine. Preferably omeprazole is used as a K ⁺ / Na ⁺ ATPase inhibitor.

The K ⁺ / Na ⁺ ATPase inhibitor or anti-H ₂ may be introduced in an outer capsule, inner capsule or other isolated pharmaceutical form. Since it is necessary to allow the K ⁺ / Na ⁺ ATPase inhibitor or the anti-H ₂ to reach the small intestine, it can also be delivered by impregnation in satellite coating pellets, a plurality of small tablets or a single tablet. Given that K ⁺ / Na ⁺ ATPase inhibitors or anti-H ₂ should be administered according to criteria different from triple therapy, according to the doctor's prescription for the severity of the disease and the patient's condition, K ⁺ / Na ⁺ by replacing the double capsules containing ATPase inhibitor or anti--H ₂ it can also be administered to double capsules which do not contain a K ⁺ / Na ⁺ ATPase inhibitor or anti--H _2.

According to another preferred embodiment of the invention, the outer capsule contains bismuth subcitrate and metronidazole, and the inner capsule contains tetracycline and omeprazole.

Features of the Invention

Both capsules preferably contain excipients. These excipients include magnesium stearate; Talc; Cellulose and its derivatives; Silica and its derivatives; Sugar; Polyethylene-glycol; Wax; Mono-, di-, and tra-glycerides of hydrogenated fatty acids; High molecular weight alcohols and acids; And these mixtures.

Both inner and outer capsules containing the above active ingredients are stable at temperatures of 5-50 ° C. and humidity of 35-65%.

Scope of the invention

Preferred embodiments of the invention for triple and quadruple treatment for eradication of Helicobacter pyrroli are described above. While such treatment is preferred for eradication of Helicobacter pyrroli, it should be understood that double capsules may contain other active ingredients. Thus, combinations of the active ingredients enumerated in the background can be used in the claimed pharmaceutical dosage forms without departing from the scope of the present invention. For example, using combination 34 listed above, dual capsules with an outer capsule containing clarithromycin and an internal capsule containing pantoprazole are also within the scope of the claimed invention.

Stability and solubility tests are described below along with examples of double capsules, but this is for illustrative purposes and does not limit the scope of the invention.

Stability test

Two products, one capsule containing tetracycline hydrochloride, bismuth biscalitrate and metronidazole in one capsule, and the tetracycline uncoated in the inner capsule and the bismuth biscalitrate and metronidazole in the outer capsule Double capsules containing were prepared and analyzed.

Samples of each product were analyzed by incubating for 1 month at room temperature, 37 ℃ and 44 ℃. Macroscopic characterization of the product was performed immediately before and after the culture.

Before incubation

Sole capsule

Outer capsule white

Contents: mixture of white powder (bismuth biscalitrate) and

Yellow Powder (Tetracycline Hydrochloride)

Double capsule

Outer capsule white

Inner capsule brown

Outer powder content: white powder (bismuth biscalitrate, metronidazole)

Internal powder content: yellow powder (tetracycline hydrochloride)

1 month later Sole capsule Room temperature 37 ℃ 44 ℃ Outer capsule Slightly yellow White White contents Mix of white and yellow powder Mix of white and beige powder Mix of white and beige powder Double capsule Room temperature 37 ℃ 44 ℃ Outer capsule White White White Inner capsule Brown Brown Brown Outer capsule contents White powder White powder White powder Inner capsule contents Yellow powder Yellow powder Yellow powder

As can be seen in Table 2. At 37 ° C. and 44 ° C., the contents of the single coated capsules formed a beige product, but the double capsules according to the present invention had no degraded product. This effect is obtained by the physical boundaries represented by the coating of the inner capsules preventing the leakage of tetracycline.

Solubility test

Five double capsules were taken in one batch, all of which had the same characteristics:

External capsule of format 0+ containing 215 mg of bismuth biscalitrate, 125 mg of metronidazole;

Inner capsule of format 3 containing 125 mg of tetracycline hydrochloride.

The solubility test was carried out under the same circumstances, respectively, according to the pharrmacolpoeia of the US USP 23 edition.

The purpose of the test is to determine the exact amount of tetracycline dissolved in the inner capsule (as described in the Pharmacopoeia, which is also in communication with other Pharmacopoeias). For accurate amounts of measurement, the presence of the outer capsule and its components should not affect the amount of material dissolved and the time taken for the release of tetracycline hydrochloride.

According to the criteria according to the pharmacopoeia, the amount of substance dissolved within 60 minutes should not be less than 80% of the amount present in the capsule.

For the double capsule, the following dissolution test results were obtained:

Minimum Melt Value: 81.4%

Max Melt Value: 107.9%

Average value: 100.0%

RSD = 9.7% (RSD = relative standard error)

From the results obtained, it is clear that the double capsules according to the invention are suitable for the dissolution properties foreseen.

Example 1

A capsule of format 3 was prepared having the following contents:

Tetracycline hydrochloride 125 mg

Gastric protected omeprazole 5 mg

Magnesium Stearate 5 mg

Talc 5 mg

A capsule of format 0+ was prepared having the following contents:

Bismuth biscalitrate 215 mg (corresponds to 53.7 mg of bismuth)

Metronidazole 125 mg

Magnesium Stearate 5 mg

Talc 5 mg

Capsule 0+ is not completely sealed, so it can be opened again using a Zuma to insert a format 3 capsule therein.

The capsules were sealed and the degradation time, average weight of the contents, sealing procedure, analysis of single components and microbial purity were adjusted in the same manner as the method according to the above pharmacopoeia.

While the preferred embodiments of the invention have been described in detail, the scope of the invention is not limited to the individual embodiments, and various modifications and changes are possible without departing from the spirit and scope of the invention.

Claims (37)

And an inner capsule positioned inside the outer capsule, wherein the outer capsule contains a soluble salt of bismuth and a first antibiotic selected from the group consisting of nitroimidazole-based compounds, and the inner capsule is macrolide. And a second antibiotic selected from the group consisting of tetracycline-based compounds, wherein the soluble salts of bismuth and the second antibiotic are physically separated and do not come into contact with each other. The method of claim 1, wherein the inner capsule further comprises BY841; Cimetidine; Ebrotidine; Ethyntidine; Pamotidine; Flunarizine; ICI-162,846; Lansoprazole; Metiamide; Mifentidine; Niferotidine; Nizatidine; Omeprazole; Oxmetidine; Pantoprazole; Rabeprazole; Lamyxotidine; Ranitidine; Ritinine; Roxatidine acetate hydrochloride; ZKF-93479; SKF-94482; Supotidine; Thiotidine; TY-11345; Wy-45,727; And double capsules for quadruple treatment of microbial Helicobacter pyrroli containing an anti-H ₂ or K ⁺ / Na ⁺ ATPase inhibitor selected from the group consisting of zaltidine. The method of claim 1, wherein the outer capsule further comprises BY841; Cimetidine; Ebrotidine; Ethyntidine; Pamotidine; Flunarizine; ICI-162,846; Lansoprazole; Metiamide; Mifentidine; Niferotidine; Nizatidine; Omeprazole; Oxmetidine; Pantoprazole; Rabeprazole; Lamyxotidine; Ranitidine; Ritinine; Roxatidine acetate hydrochloride; ZKF-93479; SKF-94482; Supotidine; Thiotidine; TY-11345; Wy-45,727; And a double-capsule for quadruple treatment of microbial Helicobacter pyrroli containing an anti-H ₂ or K ⁺ / Na ⁺ ATPase inhibitor selected from the group consisting of zaltidine. The method of claim 1, further comprising BY841; Cimetidine; Ebrotidine; Ethyntidine; Pamotidine; Flunarizine; ICI-162,846; Lansoprazole; Metiamide; Mifentidine; Niferotidine; Nizatidine; Omeprazole; Oxmetidine; Pantoprazole; Rabeprazole; Lamyxotidine; Ranitidine; Ritinine; Roxatidine acetate hydrochloride; ZKF-93479; SKF-94482; Supotidine; Thiotidine; TY-11345; Wy-45,727; And an anti-H ₂ or K ⁺ / Na ⁺ ATPase inhibitor selected from the group consisting of zaltidine in a separate formulation, a double capsule for quadruple treatment of microbial Helicobacter pyrroli. The method of claim 1, The bismuth salts are bismuth subcitrate, bismuth aluminate, bismuth carbonate, bismuth citrate, colloidal bismuth subnitrate, bismuth germanate, bismuth germanium oxide, bismuth nitrate, bismuth oxide, bismuth oxychloride, bismuth phosphate , Bismuth salicylate, bismuth subcarbonate, bismuth subnitrate, bismuth subsalicylate, bismuth tribromophenate, bismuth trioxide, bismuth vanadate and bismuth vanadium tetraoxide; Said first antibiotic is nitroimidazole; The second antibiotic is selected from the group consisting of macrolides and tetracycline compounds. The method of claim 5, The nitroimidazoles are metronidazole, apronidazole, azomycin, benzonidazole, carnidazole, demethidazole, ethanidazole, flunidazole, misnidazole, nimorazol, ornidazole, panidazole , Selected from the group consisting of ronidazole and tinidazole; The macrolide is selected from the group consisting of azithromycin, clarithromycin and erythromycin; The said tetracycline-based compound is a double capsule selected from the group consisting of tetracycline, chlortetracycline, doxycycline, glycocycline, guamecycline, limethiclin, methacycline and sancycline. The method of claim 6, The salt of bismuth is bismuth subcitrate; Said first antibiotic is metronidazole; Double capsule, wherein said second antibiotic is tetracycline. The method of claim 2, The bismuth salts are bismuth subcitrate, bismuth aluminate, bismuth carbonate, bismuth citrate, colloidal bismuth subnitrate, bismuth germanate, bismuth germanium oxide, bismuth nitrate, bismuth oxide, bismuth oxychloride, bismuth phosphate , Bismuth salicylate, bismuth subcarbonate, bismuth subnitrate, bismuth subsalicylate, bismuth tribromophenate, bismuth trioxide, bismuth vanadate and bismuth vanadium tetraoxide Said first antibiotic is nitroimidazole; The second antibiotic is selected from the group consisting of macrolides and tetracycline compounds. The method of claim 8, The nitroimidazoles are metronidazole, apronidazole, azomycin, benzonidazole, carnidazole, demethidazole, ethanidazole, flunidazole, misnidazole, nimorazol, ornidazole, panidazole , Selected from the group consisting of ronidazole and tinidazole; The macrolide is selected from the group consisting of azithromycin, clarithromycin and erythromycin; The said tetracycline-based compound is a double capsule selected from the group consisting of tetracycline, chlortetracycline, doxycycline, glycocycline, guamecycline, remethiclin, metacycline and sancycline. The method of claim 9, The salt of bismuth is bismuth subcitrate; The first antibiotic is metronidazole; The second antibiotic is tetracycline A double capsule in which the K ⁺ / Na ⁺ ATPase inhibitor or anti-H ₂ is an omeprazole. The method of claim 3, wherein The bismuth salts are bismuth subcitrate, bismuth aluminate, bismuth carbonate, bismuth citrate, colloidal bismuth subnitrate, bismuth germanate, bismuth germanium oxide, bismuth nitrate, bismuth oxide, bismuth oxychloride, bismuth phosphate , Bismuth salicylate, bismuth subcarbonate, bismuth subnitrate, bismuth subsalicylate, bismuth tribromophenate, bismuth trioxide, bismuth vanadate and bismuth vanadium tetraoxide Said first antibiotic is nitroimidazole; The second antibiotic is selected from the group consisting of macrolides and tetracycline compounds. The method of claim 11, The nitroimidazoles are metronidazole, apronidazole, azomycin, benzonidazole, carnidazole, demethidazole, ethanidazole, flunidazole, misnidazole, nimorazol, ornidazole, panidazole , Selected from the group consisting of ronidazole and tinidazole; The macrolide is selected from the group consisting of azithromycin, clarithromycin and erythromycin; The said tetracycline-based compound is a double capsule selected from the group consisting of tetracycline, chlortetracycline, doxycycline, glycocycline, guamecycline, limethiclin, methacycline and sancycline. The method of claim 12, The salt of bismuth is bismuth subcitrate; The first antibiotic is metronidazole; The second antibiotic is tetracycline A double capsule in which the K ⁺ / Na ⁺ ATPase inhibitor or anti-H ₂ is omeprazole. The method of claim 4, wherein The bismuth salts are bismuth subcitrate, bismuth aluminate, bismuth carbonate, bismuth citrate, colloidal bismuth subnitrate, bismuth germanate, bismuth germanium oxide, bismuth nitrate, bismuth oxide, bismuth oxychloride, bismuth phosphate , Bismuth salicylate, bismuth subcarbonate, bismuth subnitrate, bismuth subsalicylate, bismuth tribromophenate, bismuth trioxide, bismuth vanadate and bismuth vanadium tetraoxide, Said first antibiotic is nitroimidazole; The second antibiotic is selected from the group consisting of macrolides and tetracycline compounds. The method of claim 14, The nitroimidazoles are metronidazole, apronidazole, azomycin, benzonidazole, carnidazole, demethidazole, ethanidazole, flunidazole, misnidazole, nimorazol, ornidazole, panidazole , Selected from the group consisting of ronidazole and tinidazole; The macrolide is selected from the group consisting of azithromycin, clarithromycin and erythromycin; The said tetracycline-based compound is a double capsule selected from the group consisting of tetracycline, chlortetracycline, doxycycline, glycocycline, guamecycline, limethiclin, methacycline and sancycline. The method of claim 15, The salt of bismuth is bismuth subcitrate; The first antibiotic is metronidazole; The second antibiotic is tetracycline A double capsule in which the K ⁺ / Na ⁺ ATPase inhibitor or anti-H ₂ is an omeprazole. The double capsule of claim 1, wherein both the inner and outer capsules are stable at a temperature of 5-50 ° C. and a humidity of 35-65%. The double capsule of claim 1, wherein both the inner and outer capsules are made of hard gelatin. The dual capsule of claim 1, wherein the inner capsule has a format between 2 or 3, and the outer capsule has a format between 0+ or 1. 20. The dual capsule of claim 19 wherein the outer capsule has a format of 0+ and the inner capsule has format 3. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete The method of claim 1, wherein the inner and outer capsules are each independently magnesium stearate; Talc; Cellulose and its derivatives; Silica and its derivatives; Sugar; Polyethylene glycol; Wax; Mono-, di-, and tri-glycerides of hydrogenated fatty acids; High molecular weight alcohols and acids; And an excipient selected from the group consisting of these mixtures. delete